| Objective: Thyroid is an important endocrine organ in the human body.Subclinical hypothyroidism(SCH)is the most common pregnancy-related thyroid disease.Normal thyroid function is necessary for the reproductive process.If there is a pathological change in maternal thyroid function,clinical studies will show that clinical hypothyroidism in pregnant women is associated with an increased risk of spontaneous abortion.Abortion is one of the common complications of pregnancy,with an incidence of 10 to 15%.Subclinical hypothyroidism affects 3 to 27.8% of pregnant women,and its role in spontaneous abortion has received attention.The optimal cut-off value of TSH in pregnant women and the mechanism of spontaneous abortion caused by subclinical hypothyroidism are not clear.In addition,hypothyroidism is currently the most common thyroid dysfunction in adults.The purpose of our study is to assess the prevalence and risk factors of hypothyroidism,and to provide a basis for the prevention of hypothyroidism.Methods:Part IWe conducted a case-control study based on the study of The Subclinical Hypothyroid in Early Pregnancy Study(SHEP)in early pregnancy.Thyroid stimulating hormone(TSH),free thyroxine(FT4),thyroid peroxidase antibody(TPOAb)and thyroglobulin antibody(TgAb),urine iodine,and urine creatinine were measured.The questionnaire includes a history of motherhood,a personal and family history of thyroid disease,a history of smoking,a history of drinking,family income,and education.Finally,we included 421 cases and 1684 controls for the final analysis.Part II150 healthy female Wistar rats were randomly divided into 3 groups(n = 50).Normal control group(CON): thyroidectomy sham surgery,one month after surgery,the same volume of normal saline was injected subcutaneously in the neck and back;subclinical hypothyroidism group(SCH): thyroid surgery was completely removed,one month after surgery Continuous daily subcutaneous injection of levothyroxine in the neck and back;clinical hypothyroidism(OH)group: total thyroidectomy was performed,and one volume of daily subcutaneous injection in the neck and back was performed one month after surgery Saline.The establishment of animal models was verified by measuring the concentrations of serum TSH and TT4.After successful modeling,female rats and male rats were caged at a ratio of 2: 1,and female rats with sperm observed under a vaginal smear microscope were deemed to have successfully conceived..On day 0(E0)of pregnancy,day 5(E5)of pregnancy,and day 13(E13)of pregnancy,they were sacrificed and tissues were removed.The number of implantation sites was observed on day E5,the embryo absorption was observed on day E13,and the embryo absorption rate was counted.HE staining was used to observe the morphology of placenta.Detection of tumor necrosis factor α(TNFα),glucose transporter 1(GLUT1),glucose transporter 2(GLUT2),glucose transporter 4(GLUT4)by E-,E5,E13 uterus and placenta on day 13 by RT-PCR,Peroxidase Proliferator Activated Receptor(PPARγ),Silencing Information Regulatory Transcription Factor(SIRT1),Peroxisome Proliferator Activated Receptor γ Coactivator α(PGC1α),Hypoxia Inducible Factor(HIF-1α),MRNA expression of vascular endothelial growth factor(VEGF).Western blot was used to detect the protein expression levels of VEGF,matrix metalloproteinase 2(MMP2),and matrix metalloproteinase 9(MMP9).Immunofluorescence method was used to detect the protein expression of placenta in E13 day.Statistical software SPSS 23.0 was used to statistically analyze the differences between the groups.Part IIIThe TIDE study is a cross-sectional study of adults aged 18 or over from 31 provinces,autonomous regions and municipalities in mainland China.This study uses multi-stage stratified sampling.The entire study was conducted in four phases of random sampling in parallel from urban and rural areas.The standard questionnaire includes demographic variables,personal and family history of thyroid disease,current smoking status,family income,education level,and iodized salt intake.This study collected fasting blood and urine samples from each respondent.Chemiluminescence immunoassay was used to detect serum thyroid stimulating hormone,thyroid peroxidase antibody and thyroglobulin antibody.When thyroid stimulating hormone is outside the reference range,free thyroxine and free triiodothyroxine are measured.Urinary iodine was determined using inductively coupled plasma mass spectrometry.Result:Part IWe found that higher TSH was associated with spontaneous abortion(OR 1.21;95% CI,1.13-1.30,p <0.001).It was found that compared with TSH 1.04-<1.60 mIU / L,the risk of spontaneous abortion in the TSH 1.60-<2.17 mIU / L group was 1.56 times,TSH 2.17-<3.04 mIU / L group was 2.06 times the risk,and TSH ≥ 3.04 mIU / L group risk was 2.14 times.After adjusting for age,smoking history,drinking history,BMI,abortion history,and hypertension,the results were similar to those before.Even in women with TPOAb-negative pregnancy,the risk of spontaneous abortion was increased in the TSH 1.60-<2.17 m IU / L group(OR 1.57;95% CI,1.08-2.29,p = 0.015),TSH 2.17-<3.04 mIU / L risk was higher(OR,2.18;95% CI,1.52-3.12,p <0.001),and TSH ≥ 3.04 mIU / L risk was 2.11 times(95% CI 1.51,1.46-3.05,p <0.001).This indicates that TSH is in the range of 1.6-2.17 m IU / L,and the risk of spontaneous abortion has increased.Therefore,we further explored the cutoff value of serum TSH in early pregnancy.The cut-off point of serum TSH for predicting spontaneous abortion in early pregnancy was 1.9 mIU / L,the sensitivity was 62.2%,the specificity was 54.6%,and the area under the diagnostic ROC curve was 0.599.Taking non-abortion and thyroid antibody negative patients as a reference,the cut-off values for TSH predicting thyroid antibody positive,TPOAb positive,TgAb positive,TPOAb and TgAb positive,and spontaneous abortion in thyroid antibody negative patients were 2.86 mIU / L and 2.97 m IU / L,2.11 m IU / L,3.22 mIU / L,1.96 mIU / L;sensitivity is 52.5%,57.4%,70.7%,60%,57.8%;specificity is 81.4%,82.8%,64.2%,86.5 %,59.9%;the area under the diagnostic ROC curve was 0.708,0.734,0.729,0.805,0.602.It can be seen that the cutoff value of serum TSH in early pregnancy is 1.9-3.22 mIU / L.Serum TSH is more effective in predicting spontaneous abortion in thyroid antibody-positive people,and it is the best in those who are positive for TPOAb and TgAb.Part II1.Compared with the CON group,the serum TSH level in the SCH group and the OH group was significantly increased(P <0.05),while TT4 was significantly decreased(P <0.05),indicating that the total thyroidectomy was successful.In the SCH group,the serum TT4 level of rats returned to normal levels after continuous injection of levothyroxine for 9 days,and the TSH level was higher than that in the CON group,indicating that the model of subclinical hypothyroidism was successfully established.TT4 was significantly lower than that in the CON group,indicating that the clinical model of hypothyroidism was successful.When sacrifice on GO,G5 and G13 days,the serum TSH of pregnant mice in SCH group was higher than that in CON group(p <0.05),and there was no statistical difference between TT4 and CON group(p> 0.05);In the CON group(p <0.05),TT4 was less than the minimum value,suggesting that the three groups were successfully modeled and remained stable throughout pregnancy.2.The number of embryo implantation sites in the OH group and the SCH group on the E5 day was significantly lower than that in the CON group(P <0.05).3.Use HE staining method to further observe and analyze the placenta tissue morphology.The results showed that compared with the CON group,the total area of the placenta in the CH group and the SCH group was reduced(p <0.05),but the ratio of each area to the total area was not statistically different(p> 0.05).4.Compared with the CON group,the uterine TNFα mRNA expression of E0 in the SCH group and the OH group was significantly increased(p <0.05);the SCH group of E5 uterine TNFα m RNA expression was significantly increased,and the OH group was significantly reduced(p <0.05);there was no significant difference in TNFα mRNA expression among the three groups in E13 uterus.The expression of TNFα mRNA in the placenta of the SCH group and the OH group at day E13 was higher than that in the CON group,and there was a statistical difference between the OH group(p <0.05).5.Compared with the CON group and the SCH group,the expression of GLUT1 mRNA in the uterus of E5 in the OH group was significantly increased(p <0.05);there was no significant difference in the expression of GLUT1 mRNA in the three groups of E0,E13 uterus and E13 placental tissue.6.Compared with the CON group and the SCH group,the expression of GLUT2 mRNA in the uterus of E5 in the OH group was significantly reduced(p <0.05);there was no significant difference in the expression of GLUT2 mRNA in the three groups in the E0,E13 uterus and E13 placental tissues.7.Compared with the CON group and the SCH group,the expression of GLUT4 mRNA in the uterus of E5 rats in the OH group was significantly reduced(p <0.05);the expression of GLUT4 in the SCH group was higher than that in the CON group on days E0 and E5;The mRNA expression was significantly lower than that in the OH group(p <0.05),and there was no statistical difference compared with the CON group.8.Compared with the CON group,the expression of PPARγ mRNA in the uterus of E0,E5,and E13 in the SCH group increased;the expression of PPARγ mRNA in the SCH group and the OH group was higher in the SCH group than in the CON group.9.Compared with the CON group,the uterine SIRT1 mRNA expression levels of E0 and E5 in the SCH group were reduced,but there was no statistical significance;in the E13 placental tissue,the SIRT1 mRNA expression levels of the SCH group and the OH group were higher than those in the CON group,and there was no statistical difference.10.Compared with the CON group,the expression of PGC1α mRNA in the uterus of E0 and E5 rats in the SCH group was reduced,but there was no statistical significance.The uterine PGC1α mRNA of the OH group in the E5 day was lower than that in the CON group and the SCH group(p <0.05).The expression of PGC1α mRNA in E13 placenta tissue was higher in SCH group and OH group than in CON group,and the difference was not statistically significant.11.Compared with the CON group and the SCH group,the expression of HIF1α mRNA in the uterus of E5 rats in the OH group was significantly increased(p <0.05);the expression of HIF1α mRNA in the SCH group in the placental tissue of E13 was higher than that in the CON group and the OH group.No statistical significance.12.The expression of VEGF,MMP2 and MMP9 in the placenta of subclinical hypothyroidism and clinical hypothyroidism rats was significantly lower than that of the normal control group(P <0.05).There was no significant difference between the subclinical hypothyroidism and the clinical hypothyroidism group.Part III80,937 people participated in the study,of which 78,470(38,182 men and 40,188 women)were included in the final analysis.The prevalence of hyperthyrotropinemia was 14.11%,the prevalence of OH,severe SCH,and mild SCH were 1.02%,0.75%,and 12.18% respectively,women were higher than men,and this gender difference was noted among all age groups.In the multivariate logistic regression model,TPOAb,TgAb,age,female,family history of thyroid disease were associated with OH and SCH.Among euthyroid people,mild SCH,severe SCH,and OH patients,TPOAb or/and TgAb positive rates were 10.3%,24.1%,46.5% and 59.2%,respectively(p<0.001).With the increase of urinary iodine levels,the risk of mild SCH was increased which only found in antibody-negative and female patients.In non-autoimmune and male populations,the prevalence of severe SCH and OH was U-shaped with UIC.Conclusion:Pregnant women with elevated TSH levels have an increased risk of spontaneous abortion in early pregnancy.TSH level between 1.60-<2.17 mIU / L will increase the risk of miscarriage,and TSH greater than 2.17 m IU / L will further increase the risk of miscarriage.High serum TSH can predict the occurrence of spontaneous abortion,and the diagnostic value is higher in thyroid antibody-positive people.Increased TSH in pregnant rats may affect placental energy metabolism and nutrient transport by up-regulating PPARγ,SIRT1,PGC-1α,and down-regulating GLUT2 and GLUT4.Down-regulating VEGF,MMP2,and MMP9 affects vascular remodeling and invasion,making the pregnancy process unsustainable.This can cause miscarriages.Subclinical hypothyroidism is the most common form of hyperthyrotropinemia.Severe subclinical hypothyroidism is more prone to clinical hypothyroidism.Women,aging,family history of thyroid disease,TPOAb and TgAb positive are the main risk factors for hypothyroidism.In the case of negative thyroid autoantibodies,the prevalence of hypothyroidism increases with increasing iodine concentration,and the effect on mild subclinical hypothyroidism is more obvious. |
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